Treatment for Depression After Unsatisfactory Response to SSRIs in Adults and Adolescents

Treatment for Depression After Unsatisfactory Response

to SSRIs in Adults and Adolescents

Prepared for:Agency for Healthcare Research and Quality (AHRQ)

www.ahrq.gov

Depressions is a complex mental illness that is associated with: Disability Reduced quality of life for the person with depression Substantial societal burden

It is common among adults and adolescents. It is characterized by chronic, recurrent episodes

that significantly impact disability and mortality.

Background: Depression

Santaguida P, MacQueen G, Keshavarz H, et al. AHRQ Comparative Effectiveness Review No. 62. Available at http://www.effectivehealthcare.ahrq.gov/ssri-depression.cfm.

Major depressive disorder (MDD): characterized by the occurrence of one or more major depressive episodes.

Dysthymic disorder: characterized by the presence of depression symptoms more often than not for at least 2 years. However, symptoms are insufficient to meet MDD criteria.

Subsyndromal depression: subthreshold depression, defined by some professional groups as having at least two depressive symptoms from those listed in the DSM-IV-TR but insufficient symptoms to meet MDD criteria.

Background: Depressive Disorders

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. 1994.Cuijpers P, Smit F. Acta Psychiatr Scand. 2004;109(5):325-31. PMID: 15049768.Gartlehner G, Thaler K, Hill S, et al. Curr Psychiatry Rep. 2012;14(4):360-9. PMID: 22648236.Judd LL, Akiskal HS, Paulus MP. J Affect Disord. 1997;45(1-2):5-17. PMID: 9268771.Lavretsky H, Kumar A. Am J Geriatr Psychiatry. 2002;10(3):239-55. PMID: 11994211.Olfson M, Broadhead WE, Weissman MM, et al. Arch Gen Psychiatry. 1996;53(10):880-6. PMID: 8857864.Rapaport MH, Judd LL, Schettler PJ, et al. Am J Psychiatry. 2002;159(4):637-43. PMID: 11925303.Santaguida P, MacQueen G, Keshavarz H, et al. AHRQ Comparative Effectiveness Review No. 62. Available at http://www.effectivehealthcare.ahrq.gov/ssri-depression.cfm.

Depression among adults in the United States has an estimated lifetime prevalence of 16 percent and an estimated annual prevalence of 7 percent.

The prevalence of major depressive disorder in adolescents, 12 to 16 years of age, varies from 4 to 8 percent but has been reported to be as high as 20 percent.

Risk of depression increases following puberty, especially in girls relative to boys (2:1 ratio).

Reports of dysthymia prevalence vary from 1.6 to 8 percent. Adolescents with depression have high rates of comorbid

psychiatric conditions (reports vary from 40% to 90%).

Background: Prevalence of Depressive Disorders

Beck CA, Patten SB. Compr Psychiatry. 2004;45(4):268-74. PMID: 15224269.Birmaher B, Brent D, Bernet W, et al. J Am Acad Child Adolesc Psychiatry. 2007;46(11):1503-26. PMID: 18049300.Birmaher B, Ryan ND, Williamson DE, et al. J Am Acad Child Adolesc Psychiatry. 1996;35(12):1575-83. PMID: 8973063.Brugha T, Jenkins R, Bebbington P, et al. Soc Psychiatry Psychiatr Epidemiol. 2004;39(12):939-46. PMID: 15583900.Kessler RC, Berglund P, Demler O, et al. JAMA. 2003;289(23):3095-105. PMID: 12813115.Kessler RC, Demler O, Frank RG, et al. N Engl J Med. 2005;352(24):2515-23. PMID: 15958807.US Preventive Services Task Force. J Am Acad Pediatr. 2009;123(4):1223-8. PMID: 19336383.

Major depressive disorder is a leading cause of disability throughout the world.

The economic burden of depression is estimated to be $83.1 billion per year.

Depressive disorders negatively affect quality of life: Negative effect on children and family dynamics Negative impact on occupational/school functioning Negative impact on physical health

Reduced treatment adherence and preventative activities Increased risk factors (e.g., obesity, smoking, sedentary

lifestyle) Increase in chronic disease incidence Increased mortality rates and suicide

Background: Disease Burden Associated With Major Depressive Disorder


Depression is frequently underdiagnosed in primary practice. Only an estimated 42 percent of adult patients with major

depression were diagnosed by primary care physicians. Primary care physicians encounter a broad spectrum of

depressive symptoms. A comparative study found no major differences in

benefits between several instruments used for monitoring depressive symptoms.

Patients in primary care may not be receptive to suggested treatment for a condition that was not the reason for the visit to the physician.

Background: Clinical Assessment

Rush AJ, Trivedi MH, Wisniewski SR, et al. N Engl J Med. 2006;354(12):1231-42. PMID: 16554525.Santaguida P, MacQueen G, Keshavarz H, et al. AHRQ Comparative Effectiveness Review No. 62. Available at http://www.effectivehealthcare.ahrq.gov/ssri-depression.cfm.Williams JW, Pignone M, Ramirez G, et al. Gen Hosp Psychiatry. 2002;24(4):225-37. PMID: 12100833.

Acute phase Elimination of symptoms of depression and the

restoration of psychosocial functioning with a target goal of remission

Continuation phase Prolongation of treatment from 4 to 9 months to

completely resolve a depressive episode Maintenance phase

Prevention of recurrence of new episodes of major depressive disorder

Background: Three Phases of Treatment for Major Depressive Disorder

Kupfer DJ. J Clin Psychiatry. 1991;52 Suppl:28-34. PMID: 1903134.McIntyre RS, Fallu A, Konarski JZ, et al. Clin Ther. 2006;28(11):1882-91. PMID: 17213009.Paykel ES, Ramana R, Cooper Z, et al. Psychol Med. 1995;25(6):1171-80. PMID: 8637947.

Pharmacological agents are one of several treatment modalities used for depression.

Selective serotonin-reuptake inhibitors (SSRIs) are frequently used to treat depression. A 50-percent decrease in symptom severity

constitutes a response to SSRIs. Remission is defined as free or nearly free of

symptoms for the current episode.

Background: Pharmacological Treatment for Major Depressive Disorder

Carvalho AF, Cavalcante JL, Castelo MS, et al. J Clin Pharm Ther. 2007;32(5):415-28. PMID: 17875106.McIntyre RS, Fallu A, Konarski JZ. Clin Ther. 2006;28(11):1882-91. PMID: 17213009.Souery D, Papakostas GI, Trivedi MH. J Clin Psychiatry. 2006;67(Suppl 6):16-22. PMID: 16848672.

Although patients with major depressive disorder have a 63-percent response rate during 6 to 12 weeks of treatment with second-generation antidepressants, 53 percent did not achieve remission.

Additionally, up to two-thirds of patients may not achieve remission with a selective serotonin-reuptake inhibitor (SSRI), a commonly used class of second-generation antidepressants.

In a review on the efficacy of treatment for adolescents, those failing to respond to an initial trial of SSRIs varied from 31 to 64 percent.

Up to 60 percent of adolescents on combined treatment for depression respond positively to these interventions.

Background: Inadequate Response to Selective Serotonin-Reuptake Inhibitors

Brent D, Emslie G, Clarke G, et al. JAMA. 2008;299(8):901-13. PMID: 18314433.Gartlehner G, Hansen R, Morgan LC, et al. Ann Intern Med. 2011;155:772-85. PMID: 22147715.Perahia DG, Quail D, Desaiah D. J Psychiatr Res. 2009;43(5):512-8. PMID: 18707693.Souery D, Papakostas GI, Trivedi MH. J Clin Psychiatry. 2006;67(Suppl 6):16-22. 3. PMID: 16848672.Trivedi MH, Greer TL, Grannemann BD, et al. J Psychiatr Pract. 2006;12(4):205-13. PMID: 16883145.Williams AL, Girard C, Jui D, et al. Clin Invest Med. 2005;28(3):132-9. PMID: 16021987.

Some patients who have an inadequate response may go on to have their depression defined as treatment resistant if they do not respond to subsequent treatments.

Treatment resistance usually describes depression that has not responded to at least two trials of medication that have been of adequate dose and duration.

Nonadherence may account for up to 20 percent of patients classified as having treatment-resistant depression.

Heterogeneity exists across studies that evaluate the efficacy of selective serotonin-reuptake inhibitors within this patient population.

Background: Treatment-Resistant Depression

Berlim MT, Fleck MP, Turecki G. Ann Med. 2008;40(2):149-59. PMID: 18293145.Souery D, Amsterdam J, de Montigny C, et al. Eur Neuropsychopharmacol. 1999;9(1-2):83-91. PMID: 10082232.

Background: Different Treatment Options After an Inadequate Response to Selective Serotonin-Reuptake Inhibitors Monotherapy options

Using an optimization strategy

Switching to another selective serotonin-reuptake inhibitor (SSRI)

Switching to another class of antidepressants

Switching to a nonpharmacological intervention

Combination or add-on therapy options: Adding medications (e.g.,

augmenting agents, a different SSRI, or other antidepressants)

Switching to another agent (e.g., a different SSRI) and adding another medication

Adding a nonpharmacological treatment

Combinations of these treatmentsFava M. Biol Psychiatry. 2003;53(8):649-59. PMID: 12706951.


A variety of treatment strategies aimed at helping individuals who have inadequate responses to selective serotonin-reuptake inhibitors (SSRIs) have been studied in patients with depression.

Primary goals of the comparative effectiveness review (CER) include: Examining the evidence guiding clinical treatment decisions Aiding clinicians in their care of patients when SSRI therapy does not

result in an adequate treatment response This CME activity will summarize these results from the CER:

The range of recommended clinical actions following failure of an adequate course of an SSRI based on clinical practice guidelines

Benefits/adverse effects of monotherapy and combination therapies for adults whose depression failed to improve on an SSRI

How the therapies compare in different populations

Scope and Purpose of the Comparative Effectiveness Review on Treatments for Depression After Unsatisfactory Response to a Selective Serotonin-Reuptake Inhibitor


Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, the public, and others.

A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment.

The results of these reviews are summarized into Clinician Research Summaries and Consumer Research Summaries for use in decisionmaking and in discussions with patients. The research reviews and the full report, with references for included and excluded studies, are available at http://www.effectivehealthcare.ahrq.gov/ssri-depression.cfm.

Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development


The strength of evidence was classified into four broad categories:

Rating the Strength of Evidence From the Comparative Effectiveness Review

AHRQ Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Available at http://www.effectivehealthcare.ahrq.gov/methodsguide.cfm.Brozek J, Oxman A, Schünemann H. GRADEpro [computer program]. Version 3.2 for Windows. Available at http://www.cc-ims.net/revman/other-resources/gradepro/gradepro.Santaguida P, MacQueen G, Keshavarz H, et al. AHRQ Comparative Effectiveness Review No. 62. Available at http://www.effectivehealthcare.ahrq.gov/ssri-depression.cfm.

High High confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect.

Moderate Moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of effect and may change the estimate.

Low Low confidence that the evidence reflects the true effect. Further research is likely to change our confidence in the estimate of effect and is likely to change the estimate.

Insufficient

Evidence is either unavailable or does not permit a conclusion.

SSRI* Interventions Eligible for Inclusion in the Comparative Effectiveness Review


Citalopram (Celexa®) Escitalopram (Lexapro®) Fluoxetine (Prozac®, Prozac Weekly®, Sarafem®, and

Symbyax®) Fluvoxamine (Luvox® and Luvox CR®) Paroxetine (Paxil®, Paxil CR®, and Pexeva®) Sertraline (Zoloft®)*Concomitant use of selective serotonin-reuptake inhibitors (SSRIs) in patients taking monoamine oxidase inhibitors (MAOIs; e.g., phenelzine [Nardil®], selegiline transdermal system [EMSAM®], tranylcypromine [Parnate®]) is contraindicated, as cases of serious and sometimes fatal reactions have been reported. These reactions have also been reported in patients who have recently discontinued an SSRI or other drugs that interfere with serotonin metabolism and have been started on an MAOI. For additional information, see the U.S. Food and Drug Administration safety announcements at www.fda.gov.

Non-SSRI Antidepressants Eligible for Inclusion in the Comparative Effectiveness Review (1 of 2) Amitriptyline and its combination with other drugs

(Amitid®, Amitril®, Elavil®, Endep®, Etrafon 2-10, Etrafon 2-25, Etrafon-a, Etrafon-Forte, Limbitrol®, Limbitrol DS®, Perphenazine®, Triavil 2-10, Triavil 2-25, and Triavil 4-10)

Bupropion (Aplenzin®, Wellbutrin®, Wellbutrin SR®, Wellbutrin XL®, and Zyban®)

Clomipramine (Anafranil®) Desipramine (Norpramin® and Pertofrane®) Desvenlafaxine (Pristiq®) Doxepin (Sinequan® and Zonalon®) Duloxetine (Cymbalta®)


Non-SSRI Antidepressants Eligible for Inclusion in the Comparative Effectiveness Review (2 of 2) Imipramine (Janimine®, Presamine®, Tofranil®,

Tofranil-PM®) Maprotiline (Ludiomil®) Mirtazapine (Remeron® and Remeron SolTab®) Phenelzine (Nardil®) Protriptyline (Vivactil®) Selegiline transdermal system (EMSAM®) Tranylcypromine (Parnate®) Trazodone (Desyrel® and Trialodine®) Trimipramine (Surmontil®) Venlafaxine (Effexor® and Effexor XR®)


Nonantidepressant and Nonpharmacological Interventions Eligible for Inclusion in the CER Nonantidepressant

agents Anticonvulsants Antiprogestational agents Dopamine agonists Psychostimulants Sex hormones Thyroid medications Other drugs such as

buspirone (Buspar®), lithium, pindolol, and tryptophan

Atypical antipsychotics* Aripiprazole (Abilify®) Olanzapine (Zyprexa®) Quetiapine (Seroquel®) Risperidone (Risperdal®) Ziprasidone (Geodon®)

Nonpharmacological therapies Cognitive behavioral

therapy Exercise Interpersonal therapy Other psychotherapies


A number of outcomes are used within primary care and psychiatry to assess and monitor response to treatment.

Outcomes may be assessed with self-report instruments or scales that are completed by the clinician.

Outcome assessment is usually conducted with validated interviewer-rated scales such as the Hamilton Depression Rating Scale or the Montgomery-Asberg Depression Scale.

Response is typically defined as a greater than 50-percent reduction in scores on these scales.

Remission is defined as a score within the normal range on these scales.

Outcomes of Importance


Analysis of Clinical Practice Guidelines Monotherapy options

Optimizing the current selective serotonin-reuptake inhibitor (SSRI)

Switching monotherapy agents Monotherapy versus combination therapy

Adding medications to the existing SSRI Adding medications to a new antidepressant Adding nonpharmacological treatment to the existing SSRI

Combination therapies

CER Results for Available Treatment Options for Adults and Adolescents With MDD Who Have an Inadequate Response to SSRIs


CER = comparative effectiveness review; MDD = major depressive disorder

Variations among clinical practice guidelines (CPGs) reflect the high amount of uncertainty that exists in the current evidence base.

Of the 27 CPGs reviewed (guidelines from January 2004 to April 2011), most do not specify definitions of “inadequate response.”

All 27 CPGs provide recommendations for patients with major depressive disorder, but 7 do not provide any recommendations for patients with previous inadequate responses to therapy.

Analysis of Clinical Practice Guidelines (1 of 2)


When an increase in dose or duration is recommended for adults, the change in dose or duration is not specified.

When switching to a different monotherapy agent is recommended, most CPGs do not mention a specific antidepressant.

When combination therapy is recommended, there is a greater tendency to specify the drug to be added to the antidepressants, but there is great variability in the augmenting agents recommended.

Analysis of Clinical Practice Guidelines (2 of 2)


For adolescents, nonpharmacological interventions are the preferred first-line therapy for depression.

Some clinical practice guidelines cited research done in adult populations as the basis for treatment strategies in children and adolescents.

Analysis of Clinical Practice Guidelines: Treating Adolescents With Depression


Evidence is insufficient to determine if differences exist in response and remission rates if treatment with the current selective serotonin-reuptake inhibitor (SSRI) for major depressive disorder (MDD) is maintained versus: Dose escalation of the current SSRI Switching to a different SSRI Switching to a non-SSRI antidepressant Switching to a psychological intervention (e.g.,

cognitive behavioral therapy)Strength of Evidence = Insufficient

Clinical Bottom Line for Adults With MDD: Optimizing the Current SSRI or Switching Monotherapy Agents


Adding risperidone or olanzapine to ongoing treatment with a selective serotonin-reuptake inhibitor (SSRI) for major depressive disorder (MDD) may slightly improve response and remission rates versus continuing SSRI treatment alone. Strength of Evidence = Low

Evidence is insufficient to determine if there are differences in response and remission rates for continuing monotherapy with an SSRI versus: Adding buspirone Adding other augmenting agents (e.g., lithium or mianserin) Adding a non-SSRI antidepressant: clomipramine, bupropion,

or desipramine Strength of Evidence = Insufficient

Clinical Bottom Line for Adults With MDD: Monotherapy Versus Combination Therapy—Adding Medications to the Existing SSRI


For adults with major depressive disorder (MDD), comparable results were achieved in response and remission rates for switching to a new antidepressant versus: Combining the new monotherapy with another

treatment (e.g., a new selective serotonin-reuptake inhibitor [SSRI], a non-SSRI, or nonpharmacological treatment)

Combining the new antidepressant with buspironeStrength of Evidence = Low

Clinical Bottom Line for Adults With MDD: Monotherapy Versus Combination Therapy—Adding Medications to a New Antidepressant


Evidence is insufficient to determine if there are differences in response and remission rates for continuing therapy for major depressive disorder (MDD) with a selective serotonin-reuptake inhibitor (SSRI) versus combining that SSRI with: Cognitive behavioral therapy Dialectical behavioral therapy Exercise

Strength of Evidence = Insufficient

Clinical Bottom Line for Adults With MDD: Monotherapy Versus Combination Therapy—Adding Nonpharmacological Treatment


Evidence is insufficient to determine if there are differences in response and remission rates when a selective serotonin-reuptake inhibitor (SSRI) is given in combination with another SSRI, another antidepressant, an augmenting agent, or cognitive behavioral therapy.Strength of Evidence = Insufficient

Clinical Bottom Line for Adults With Major Depressive Disorder: Combination Therapy


In general, most reported adverse effects were consistent with those typically associated with antidepressant use and were likely mild to moderate in nature. Common adverse events included headaches, dry

mouth, dizziness, weight gain, sexual dysfunction, and fatigue.

In adults with major depressive disorder, serious and severe adverse events (e.g., suicidality) were not measured or not reported in most studies, so there is insufficient evidence to compare the adverse effects of various treatment approaches.

Clinical Bottom Line for Adults With Major Depressive Disorder: Adverse Effects


For adolescents with major depressive disorder (MDD) who have an inadequate response to selective serotonin-reuptake inhibitors (SSRIs), adding cognitive behavioral therapy (CBT) may be superior to an SSRI alone. Strength of Evidence = Low

In one study of adolescents, there were no significant differences in adverse effects for patients on an SSRI or venlafaxine with or without CBT, except for an increase in skin rashes and cardiovascular events in patients on venlafaxine.

The U.S. Food and Drug Administration has issued a warning about suicidality and antidepressant drugs. There is an increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for MDD and other psychiatric disorders.

Clinical Bottom Line for Adolescents With Major Depressive Disorder


For adults with dysthymia or subsyndromal symptoms who have an inadequate response to selective serotonin-reuptake inhibitors, there is insufficient evidence to evaluate treatment approaches.

Some evidence suggests that people with concurrent anxiety symptoms have a lesser likelihood of achieving remission.

Some evidence suggests that milder depression, less family conflict, and the absence of suicidal behavior are associated with a greater likelihood of a positive treatment response in adolescents.

Additional Information


Evidence remains limited to support clinical decisionmaking about the available approaches for treating patients with major depressive disorder (MDD) who have an inadequate response to selective serotonin-reuptake inhibitors.

With only a few exceptions, evidence for adults with MDD is insufficient to guide decisionmaking for: Comparisons among monotherapies Monotherapies versus combination therapies Comparisons among combination therapies

Evidence is insufficient to evaluate interventions for adults with dysthymia or subsyndromal symptoms.

Conclusions (1 of 2)


Adding the atypical antipsychotics risperidone or olanzapine to ongoing treatment with a selective serotonin-reuptake inhibitor (SSRI) may slightly improve response and remission rates when compared with continuing SSRI treatment alone.

Low-level evidence suggests that comparable response and remission rates are obtained from switching to a new antidepressant versus combining the new antidepressant with pharmacological or nonpharmacological treatment.

For adults, most reported adverse effects were consistent with those associated with antidepressant use; however, comparative evidence is insufficient to guide decisionmaking about adverse effects in adults.

Conclusions (2 of 2)


For adolescents with major depressive disorder, low-level evidence suggests that combining an antidepressant and cognitive behavioral therapy may be superior to medication alone.

Comparative evidence is insufficient for decisionmaking about adverse effects in adolescents.

Conclusions:Adolescents With Major Depressive Disorder


Overall, few studies have evaluated the impact of different depressive diagnoses, disease severity, previous comorbidities, age, sex, and race on treatment outcomes.

There is inconsistency between studies in the definition of “inadequate response” and in the distinction between response and remission.

More studies are needed on the response and remission rates in children and adolescents to treatments subsequent to an inadequate response to a selective serotonin-reuptake inhibitor (SSRI).

Evidence is very limited on response and remission rates for patients with subsyndromal depression or dysthymia who have inadequate responses to an SSRI.

Gaps in Knowledge


The health consequences of depression The rate of treatment response following treatment with selective

serotonin-reuptake inhibitors (SSRIs) and the possibility of treatment-resistant depression

The various interventions for treating depression after an unsatisfactory response to SSRIs

Patient preferences regarding cost, nonpharmacological treatment, medication type, and potential side effects

What is known about nonpharmacological interventions for treating depression

Potential drug interactions with medications The risk of antidepressants and other medications for pregnant or

nursing women The possibility of severe adverse effects such as suicidality and that

additional resources are available from the National Suicide Prevention Lifeline at www.suicidepreventionlifeline.org or 1-800-273-8255.

What To Discuss With Your Patients


Resource for Patients Treatment Options When Your

SSRI Antidepressant Is Not Working Well is a free companion to this continuing medical education activity. It covers: Background information about

depression and unsatisfactory response to selective serotonin reuptake inhibitors

Descriptions of the types of treatments, how they work, and their potential side effects

Questions to guide a discussion with their health care provider about treatment optionsSantaguida P, MacQueen G, Keshavarz H, et al. AHRQ Comparative Effectiveness Review No. 62. Available at http://www.effectivehealthcare.ahrq.gov/ssri-depression.cfm.

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Treatment for Depression After Unsatisfactory Response to SSRIs in Adults and Adolescents

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